AZ12977847
Preclinical pharmacology
AZ12977847 is a negative allosteric modulator of human mGluR5d, human mGluR5b, canine mGluR5c and rat mGluR5 with IC50 potency of 41, 20, 41 and 54nM respectively in vitro. AZ12977847 demonstrated IC50 values >25µM at other mGluR homologues (mGluR1-4 and mGluR6-8). AZ12977847 was shown to have limited CNS exposure in rats and so is thought to be peripherally restricted. In oesophagostomised dogs, AZ12977847 achieved 50% inhibition of transient lower oesophageal sphincter relaxations at plasma compound exposures of approximately 1.5µM (unbound 0.18µM). Similar results were seen in ferrets.
Safety & tolerability profile
AZ12977847 was well tolerated in 7-day rat toxicology studies.
Mechanism of Action
Negative allosteric modulator of human mGluR5d, Metabotropic glutamate receptor 5 (mGluR5d)
Original Therapeutic Area
Other
CNS Penetrant
Low
Route of administration
Oral
Modality
Small Molecule